Cubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA.
Antimicrob Agents Chemother. 2012 Oct;56(10):5023-30. doi: 10.1128/AAC.00057-12. Epub 2012 Jul 16.
CB-183,315 is a novel lipopeptide antibiotic structurally related to daptomycin currently in phase 3 clinical development for Clostridium difficile-associated diarrhea (CDAD). We report here the in vitro mechanism of action, spontaneous resistance incidence, resistance by serial passage, time-kill kinetics, postantibiotic effect, and efficacy of CB-183,315 in a hamster model of lethal infection. In vitro data showed that CB-183,315 dissipated the membrane potential of Staphylococcus aureus without inducing changes in membrane permeability to small molecules. The rate of spontaneous resistance to CB-183,315 at 8× the MIC was below the limit of detection in C. difficile. Under selective pressure by serial passage with CB-183,315 against C. difficile, the susceptibility of the bacteria changed no more than 2-fold during 15 days of serial passages. At 16× the MIC, CB-183,315 produced a ≥3-log reduction of C. difficile in the time-kill assay. The postantibiotic effect of CB-183,315 at 8× the MIC was 0.9 h. At 80× the MIC the postantibiotic effect was more than 6 h. In the hamster model of CDAD, CB-183,315 and vancomycin both demonstrated potent efficacy in resolving initial disease onset, even at very low doses. After the conclusion of dosing, CB-183,315 and vancomycin showed a similar dose- and time-dependent pattern with respect to rates of CDAD recurrence.
CB-183,315 是一种新型脂肽抗生素，与达托霉素在结构上有关，目前处于治疗艰难梭菌相关性腹泻（CDAD）的 3 期临床开发阶段。我们在此报告其体外作用机制、自发耐药发生率、连续传代耐药性、时间杀菌动力学、抗生素后效应以及在仓鼠致死性感染模型中的疗效。体外数据表明，CB-183,315 耗散金黄色葡萄球菌的膜电位而不诱导小分子的膜通透性改变。在艰难梭菌中，CB-183,315 的自发耐药率在 8×MIC 以下低于检测限。在连续传代过程中，通过 CB-183,315 对艰难梭菌进行选择性压力，细菌的敏感性在 15 天的连续传代过程中变化不超过 2 倍。在 16×MIC 时，CB-183,315 在时间杀菌试验中使艰难梭菌减少≥3 对数。在 8×MIC 时，CB-183,315 的抗生素后效应为 0.9 h。在 80×MIC 时，抗生素后效应超过 6 h。在艰难梭菌相关性腹泻的仓鼠模型中，CB-183,315 和万古霉素都表现出很强的疗效，甚至在很低的剂量下也能迅速缓解疾病的初始发作。停药后，CB-183,315 和万古霉素在 CDAD 复发率方面表现出相似的剂量和时间依赖性模式。
